Heparan sulfate (HS) is a highly sulfated polysaccharide that occurs on the cell surface and in the extracellular matrix as proteoglycans. HS interacts with a variety of soluble ligands, such as growth factors and morphogens, as well as cell surface receptors, and thereby plays critical roles in diverse cell surface signaling event. HS is the most structurally complex glycosaminoglycan containing variable numbers of sulfate groups at the N-, 2-O-, 3-O-, and 6- O-positions of the sugar chain. HS fine structure originating from such complex patterns of sulfation often constitutes critical determinants of the binding specificity to ligands and, as a result, the biological function of HS. Although it has lon been known that HS is concentrated in synapses, the role of HS in neurophysiology and its potential relevance to neurological and mental disorders have not been satisfactorily elucidated. To address these issues, we created conditional knockout mice in which HS expression is ablated specifically in postnatal neurons. These mutant mice displayed striking recapitulation of numerous autism-related behavioral phenotypes, and HS-deficient neurons showed impaired glutamatergic synaptic transmission due to reduced recruitment of glutamate receptors to synapses. More recently, we found that HS binds neuroligins, a family of synaptic adhesion molecules that have strong implications in autism, and regulates their multimerization. In this project, we will use mouse genetics, neuronal cell biology, and state-of-the-art carbohydrate chemistry to determine the role of HS and its fine structure in neurophysiology and the pathogenesis of autism. Specific aims are: 1. Determine the biochemical property of synaptic HS and characterize its changes in response to different social conditions and in autistic brains. 2. Determine the mechanism by which HS regulates neuroligin-dependent synapse assembly and maturation. 3. Examine the physiological relevance of the neuroligin-HS interaction by mouse genetics and proteomic experiments.